BACKGROUND:: Postoperative nausea and vomiting (PONV) is a major challenge in the peri-operative setting. The incidence can be as high as 80%, and the majority of PONV symptoms among out-patients occur after discharge. This study evaluated the efficacy of an NK1 receptor antagonist (aprepitant) in reducing PONV for up to forty-eight hours in patients undergoing outpatient plastic surgery. METHODS:: A prospective, double blinded, randomized, two-arm evaluation of 150 ambulatory plastic surgical patients receiving a standardized general anesthetic including PONV prophylaxis with ondansetron and either aprepitant or placebo. Main outcome measures were occurrence of vomiting and the severity of nausea for up to 48 hrs postoperatively. RESULTS:: Overall, 9.3% of patients who received aprepitant versus 29.7% in the Group B had vomiting with the majority of vomiting episodes occurring after hospital discharge. Kaplan-Meier plot of the hazards of vomiting reveal increased incidence of emesis in patients receiving ondansetron alone compared to the combination of ondansetron and aprepitant (p = 0.006). The incidence of nausea was not significantly different in the two groups. However, severity of nausea was significantly higher in those receiving ondansetron alone compared to the group receiving the combination of ondansetron and aprepitant as measured by a peak nausea score (p = 0.014) and by MANOVA results comparing repeated VRS scores over 48 hours post-surgery (p = 0.024). CONCLUSIONS:: In patients undergoing plastic surgery, the addition of aprepitant to ondansetron significantly decreases postoperative vomiting rates and nausea severity for up to 48 hours postoperatively. LEVEL OF EVIDENCE:: Level 2 single-centered prospective randomized controlled therapeutic trial.